Synthesis of (+)-spirolaxine methyl ether

Article abstract of DOI:10.1021/jo060839i

A short and efficient synthesis of (+)-spirolaxine methyl ether, a metabolite of the fungus Sporotrichum laxum with inhibitory activity against Helicobacter pylori, is described. The synthesis has been carried out by a Prins cyclization, to obtain the [6,

Full text of DOI:10.1021/jo060839i

CHART 1
Synthesis of (+)-Spirolaxine Methyl Ether
Raffaella Nannei,† Sabrina Dallavalle,*,† Lucio Merlini,†
Adriana Bava,‡ and Gianluca Nasini‡
Dipartimento di Scienze Molecolari Agroalimentari, UniVersita`
di Milano, Via Celoria 2, 20133 Milano, and Dipartimento di
Chimica, Materiali ed Ingegneria Chimica del Politecnico,
CNR-ICRM, Via Mancinelli 7, 20131 Milano, Italy
they did not show any antibacterial activity.4 There have been
recent studies that have shown a strong relationship between
the presence of H. pylori, which lives beneath the mucus layer
of the stomach, and the development of gastric and duodenal
ulcers.5 Presently, none of the existing therapies are capable of
completely eradicating H. pylori. Therefore, spirolaxine and its
derivatives could become potential lead compounds in the
development of drugs that treat gastroduodenal disorder and for
the prevention of gastric cancer.
sabrina.dallaValle@unimi.it
ReceiVed April 21, 2006
Also, spirolaxine has been reported to exhibit cholesterol-
lowering activity.6 Moreover, recent studies have shown that it
has cytotoxic activity toward endothelial cells (BMEC and
Huvec) as well as a variety of tumor cell lines (LoVo and
HL60).7
Due to the interest shown in such molecules, we have
developed a stereoselective synthesis of 2, which may, in
principle, have value in the preparation of spirolaxine itself as
well as different analogues. Any strategy for the total synthesis
of spirolaxine must conform to the intriguing spiroketal ring
system. Development of such methods for the preparation of
this moiety gains importance due to the existence of similar
fragments in a variety of other natural products, such as
monensin A8 and calyculin.9
A short and efficient synthesis of (+)-spirolaxine methyl
ether, a metabolite of the fungus Sporotrichum laxum with
inhibitory activity against Helicobacter pylori, is described.
The synthesis has been carried out by a Prins cyclization, to
obtain the [6,5]-spiroketal system, and a Wadsworth-
Emmons condensation, applied for the installation of the
polymethylene chain on the phthalide moiety.
The retrosynthetic approach was envisioned to proceed via a
condensation of phosphonate 3 with the aldehyde 4, obtained
by the oxidation of the corresponding alcohol 5 (Scheme 1).
We envisaged that the spiroketal system could be obtained by
an oxidative cyclization of a hydroxyalkyl-substituted tetrahy-
dropyran (6). One possibility to obtain the latter was a Prins
cyclization, which is a powerful synthetic route for the construc-
tion of these six-membered tetrahydropyran derivatives.10 This
flexible methodology involves the cross coupling of an aldehyde
with an unsaturated alcohol, in the presence of a Lewis acid, to
obtain 2,6-disubstituted 4-halotetrahydropyrans. Interestingly,
most of the examples reported that a single diastereoisomer was
produced with the three substituents occupying equatorial
positions.11 A rationale for the all-cis stereoselectivity was set
(+)-Spirolaxine (1) and (+)-spirolaxine 5-O-methyl ether (2)
(Chart 1) are polyketide-derived natural substances that were
isolated years ago from the cultures of Sporotrichum laxum,
now Phanerochaete pruinosum (Basidiomycetes).1 They contain
a 3-methoxy-5-hydroxyphthalide nucleus linked to a [6,5]-
spiroketal group by a five-membered methylene chain. The
absolute configuration of (+)-spirolaxine has recently been
established to be 3R,2′′R,5′′R,7′′R by some of us.2
Along with spirolaxine, similar metabolites were isolated from
MPGA (malt-peptone-glucose agar) cultures derived from the
aforementioned fungus, which included sporotricale1,3 and
phanerosporic acid. Similar compounds recently received at-
tention for their inhibitory activity against the micro-aerophilic
Gram-negative bacterium Helicobacter pylori, described by
Dekker et al.,4 where compound 1 exhibited the best activity.
The interest of this group of derivatives was in its selectivity.
In fact, when tested against a panel of different microorganisms,
(5) Walsh, J. H.; Peterson, W., L. N. Engl. J. Med. 1995, 333, 984.
(6) Blaser, M. J. Clin. Infect. Dis. 1992, 15, 386-391.
(7) Penco, S.; Pisano, C.; Giannini, G. WO01/68070.
(8) Westley, J. W.; Blount, J. F.; Evans, R. H.; Stempel, A.; Berger, J.
J. Antibiot. 1974, 27, 597.
(9) Kato, Y.; Fusetani, N.; Matsunaga, S.; Hashimoto, K.; Fujita, S.;
Furoya, T. J. Am. Chem. Soc. 1986, 108, 2780-2781.
(10) For reviews on the Prins cyclization see: (a) Arundale, E.; Mikeska,
L. A. Chem. ReV. 1952, 52, 505-555. (b) Adams, D. R.; Bhatnagar, S. P.
Synthesis 1977, 661-672. (c) Overman, L. E., Pennington, L. D. J. Org.
Chem. 2003, 68, 7143-7157. For recent work on the Prins cyclization see:
(d) Yadav, K. V., Kumar, N. V. J. Am. Chem. Soc. 2004, 126, 8652-
8653. (e) Cossey, K. N., Funk, R. L. J. Am. Chem. Soc. 2004, 126, 12216-
12217.
† Universita` di Milano.
‡ CNR-ICRM.
(1) Arnone, A.; Assante, G.; Nasini, G.; Vajna de Pava, O. Phytochem-
istry 1990, 29, 613-616.
(2) Bava, A.; Clericuzio, M.; Giannini, G.; Malpezzi, L.; Meille, S. V.;
Nasini, G. Eur. J. Org. Chem. 2005, 2292-2296
(3) Dallavalle, S.; Merlini, L.; Nannei, R.; Nasini, G.; Bava, A. Synlett
2005, 17, 2676-2678.
(4) Dekker, K. A.; Inagaki, T.; Gootz, T. D.; Kanede, K.; Nomura, E.;
Sakakibara, T.; Sakemi, S.; Sugie, Y.; Yamauchi, Y.; Yoshikawa, N.;
Koijma, N. J. Antibiot. 1997, 50, 833-839.
(11) Coppi, L.; Ricci, A.; Taddei, M. J. Org. Chem. 1988, 53, 911-
913.
10.1021/jo060839i CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/11/2006
J. Org. Chem. 2006, 71, 6277-6280
6277

SCHEME 1
SCHEME 2 a
a Reagents and conditions: (a) (TBDM)SiCl, Et3N, DMAP, THF, rt, 18 h, 57%; (b) NaOCl, polymer-supported TEMPO, KBr, CH2Cl2, rt, 6 h, 100%; (c)
(i) 9, -78 °C, 1 h, then 1 h at rt; (ii) NaOH (3 N), H2O2 (35%), 1 h of reflux, 82%.
forth by the computational work of Alder.12 The reaction was
believed to proceed via the formation of an oxocarbenium ion
that underwent an intramolecular cyclization. The possibility
to obtain the desired tetrahydropyran in a single step and to do
so in a stereocontrolled fashion prompted us to exploit this
condensation for the purpose of synthesizing the aldehyde 4.
Since spirolaxine has R configuration at C-7′′, we needed to
perform the reaction from an appropriate, optically pure
homoallylic (R)-alcohol that carried a substituent that enabled
us to link with the phthalide moiety. The asymmetric synthesis
of alcohol 10 was successfully accomplished by using the chiral-
directing property of B-allyldiisopinocamphenylborane, follow-
ing a well-known procedure, as described by Brown.13 This
method has the advantage of providing access to both enan-
tiomers starting from 8, by using the appropriate chiral borane.
The aldehyde 814 was prepared by protection of 1,6-hexanediol
to give the monosilyl derivative 7,15 followed by oxidation with
polymer-supported TEMPO. The B-allyldiisopinocamphenyl-
borane 9 was obtained by treatment of (-)-Ipc2OCH3 with
allylmagnesium bromide at -78 °C. It was immediately
subjected to a condensation with 8 at -78 °C to furnish, after
the usual alkaline hydrogen peroxide workup, the secondary
homoallylic alcohol 10, in 82% yield and with enantiomeric
purity >96%, as confirmed by 1H NMR in the presence of the
chiral shift reagent Eu(hfc)3 (Scheme 2). The absolute config-
uration of 10 was assumed to be R, advocating that, in all the
examples reported by Brown or others,16 the addition of the
allyl group took place in the same stereochemical fashion.
With homoallylic alcohol 10 in hand, we needed a chiral
aldehyde as a second building block for the introduction of the
proper stereochemistry at C-2′′. The required aldehyde should
incorporate the hydroxyalkane side chain for the oxidative
cyclization step to give the spiroketal 5. The hemiacetal of 4-(R)-
hydroxypentanal (11) was easily obtained by the reduction with
i-Bu2AlH of (R)-γ-valerolactone,17 which recently became
commercially available. Also, the use of (S)-γ-valerolactone
allowed access to the opposite stereoisomer.
Prins cyclization was performed by using different Lewis
acids, following a procedure described by Taddei.11 We ob-
served that the use of TiCl4 in dichloromethane at a low tem-
perature afforded better yields and cleaner reaction mixtures,
leading to the desired chlorotetrahydropyran 12, with a 63%
yield after chromatographic purification (Scheme 3).
By comparing the spectroscopic data of 12 with the values
reported in the literature of similar compounds,11,18 the major
product was identified as the stereoisomer where the two alkyl
chains and the chlorine substituents were equatorial. This was
1
represented by the width at half-heigth (WH) of the H NMR
multiplets for the protons at the 2, 6, and 4 positions of the
tetrahydropyran ring, which showed a value of about 20 Hz,
meaning existence of an axial-axial coupling.11 Furthermore,
the 1H NMR chemical shift of the 4-hydrogen was at 3.9 ppm,
typical for a H in the axial position.19 These findings confirmed
that the three substituents were all in the equatorial positions,
which is in agreement with the all-cis stereochemistry.
Flash chromatography allowed the separation of 12 from a
diastereoisomer (ca. 10%). The formation of this side product
could be explained by invoking a competitive oxo-Cope
rearrangement of the intermediate oxocarbenium ion during the
intramolecular allylation step. This side reaction, which recently
came to light, is associated with the Prins cyclization reaction.
(12) Alder, R. W.; Harvey, J.N.; Oakley, M. T. J. Am. Chem. Soc. 2002,
124, 4960-4961.
(13) Brown, H. C.; Jadhav, P. K. J. Am. Chem. Soc. 1983, 105, 2092-
(16) Hoffmann, R. W.; Herold, T. Chem. Ber. 1981, 114, 375-383.
(17) Mori, K. Tetrahedron 1975, 31, 3011-3012.
2093.
(14) Sato, T.; Otera, J.; Nozaki, H. J. Org. Chem. 1993, 58, 4971-4978.
(15) McDougal, P. G.; Rico, J. G.; Oh, Y.; Condon, B. D. J. Org. Chem.
1986, 51, 3388-3390.
(18) Yadav, J. S.; Reddy, B. V. S.; Reddy, M. S.; Niranjan, N.; Prasad,
A. R. Eur. J. Org. Chem. 2003, 1779-1783.
(19) Wighfield, D. C.; Feiner, S. Can. J. Chem. 1978, 56, 789.
6278 J. Org. Chem., Vol. 71, No. 16, 2006

SCHEME 3 a
a Reagents and conditions: (a) TiCl4, CH2Cl2, -70 °C, 4 h, then -20 °C, 1 h, 63%; (b) NaBH4, DMSO, 130 °C, 8 h, 96%; (c) (PMB)Cl, NaH, DMF,
rt, 3 days, 50%; (d) HgO, I2, hν, cyclohexane, 9 h, 68%; (e) CAN, CH3CN/H2O, rt, 2 h, 68%; (f) TEMPO, KBr, NaOCl, 3 h, 100%; (g) 3, NaH, THF, rt,
24 h, 62%; (h) 10% Pd/C, AcOH, 4 h, 45%.
Partial inversion of the original C-O stereochemistry of the
homoallylic alcohol could result from this kind of reaction.20,21
The presence of an electron-rich aromatic ring, linked to the
alcohol, favors this rearrangement,22 but there is evidence that
shows it may occur also with aliphatic alcohols.23
Reductive dechlorination, using the Hutchins24 protocol
(NaBH4 in DMSO), gave tetrahydropyran 6 in good yield (96%).
Oxidative cyclization,25 mediated by HgO/I2, generated the
desired spiroketal 5 in a disappointing yield of 21%. We
reasoned that this was due to the presence of a free primary
hydroxy group at the end of the methylene chain. Hence, the
alcohol was protected as a p-methoxybenzyl ether, and the
oxidative cyclization was performed using the same conditions
described before, leading to an improved yield of 68% after
purification by column chromatography. Deprotection of the
hydroxyl moiety gave rise to compound 5. This was oxidized
with TEMPO to obtain the desired aldehyde 4, which was
condensed with the phthalide moiety.
The synthesis of the phosphonate 3 was performed, as
previously described,3 by a reaction of N,N-diethyl-2-formyl-
benzamide, obtained by ortho-lithiation-formylation of N,N-
diethylbenzamide, with chlorotrimethylsilane and triethyl phos-
phite. This was followed by a desilylation step and then a
cyclization step with methanesulfonic acid. The condensation
of the aldehyde 4 with 3 afforded the alkene 15 as a mixture of
E/Z stereoisomers.
FIGURE 1. Selected NOESY correlations for 15.
(supported by molecular modeling of the conformational prefer-
ences). NOE correlations were found between H-2′′ and H-7′′,
H-4′ and H-2′′, and H-4′′ and CH3-2′′, which is consistent with
the minimal energy conformation of (3R,2′′R,5′′R,7′′R)-15 but
not with the C-5′′ epimer. Interestingly, we did not find a
correlation between H-4′ and H-4′′, meaning that the spiroketal
epimer was not present. These observations confirmed that the
reaction generated the thermodynamically favored spirocycle,
as found in the natural product, due to the expected axial
(anomerically stabilized) preference of the five-membered-ring
oxygen.26 A summary of the results from NOE experiments,
supported by molecular modeling, is reported in Figure 1.
Finally, reduction of the double bond in AcOH, using Pd/C
(10%) as a catalyst, led to a mixture of two diastereoisomers
from which (+)-spirolaxine methyl ether 2 was separated by
preparative HPLC. Its structure was confirmed by HPLC
analysis, where it was compared with an authentic sample. All
the spectroscopic data of the obtained compound, including the
CD spectrum, matched those of an authentic sample.
The complete assignment of the spiroketal structure and
stereochemistry was aided by proton homonuclear correlation
(COSY) experiments, followed by extensive NOE experiments
In summary, a total synthesis of (+)-spirolaxine methyl ether
was designed and carried out. Crucial steps for our strategy
included a Prins cyclization, to obtain the [6,5]-spiroketal
system, and a Wadsworth-Emmons condensation, applied for
the installation of the polymethylene chain on the phthalide
moiety. When this work was already in its advanced stage, an
alternative synthesis of (+)-spirolaxine methyl ether was
reported by Robinson and Brimble.27 The Brimble synthesis
(20) Marumoto, S.; Jaber, J. J.; Vitale, J. P.; Rychnovsky, S. D. Org.
Lett. 2002, 4, 3919-3922.
(21) Crosby, S. R.; Harding, J. R.; King, C. D.; Parker, G. D.; Willis, C.
L. Org. Lett. 2002, 4, 577-580.
(22) Crosby, S. R.; Harding, J. R.; King, C. D.; Parker, G. D.; Willis, C.
L. Org. Lett. 2002, 4, 3407-3410.
(23) Jasti, R.; Anderson, C. D.; Rychnovsky, S. D. J. Am. Chem. Soc.
2005, 127, 9939-9945.
(24) Hutchins, R.; Kandasamy, D.; Dux, F., III; Maryanoff, C. A.;
Rotstein, D.; Goldsmith, B.; Burgoyne, W.; Cistone, F.; Dalessandro, J.;
Puglis, J. J. Org. Chem. 1978, 43, 2259-2267.
(26) Deslongchamps, P.; Rowan, D. D.; Pothiers, N.; Sauve`, T.;
Saunders: J. K. Can. J. Chem. 1981, 59, 1105.
(27) Robinson J. E.; Brimble, M. A. Chem. Commun. 2005, 1560-1562.
(25) Danishefsky, S. J.; Armistead, D. M.; Wincott. F. E.; Selnick, H.
G.; Hungate, R. J. Am. Chem. Soc. 1989, 111, 2967-2980.
J. Org. Chem, Vol. 71, No. 16, 2006 6279

(2′R,5′R,7′R)-5-(2′-Methyl-1′,6′-dioxaspiro[4,5]dec-7′-yl)pen-
tan-1-ol (5). A solution of HgO (89 mg, 0.41 mmol) and I2 (104
mg, 0.41 mmol) in cyclohexane (7 mL) was stirred for 10 min,
and then 6 (100 mg, 0.41 mmol) in 5 mL of cyclohexane was added.
The reaction mixture was stirred at room temperature under a 275
W light. After 9 h, the reaction was quenched with saturated
aqueous Na2S2O5, and the aqueous phase was extracted with diethyl
ether. The combined organic layers were dried over Na2SO4.
Evaporation of the solvent in vacuo followed by flash chromatog-
raphy of the residue using 95% CH2Cl2-5% acetone as eluent
required 15 steps to prepare the spiroketal moiety and 6 steps
for the phthalide moiety. The synthesis had the advantage of
coupling two moieties that already contained all the stereo-
centers, but our synthetic approach proved to be shorter. A
combination of the two routes would most likely offer the best
pathway, where varied chain lengths could be implemented and
a variety of potentially bioactive analogues (e.g., phthalide
moiety with other substituents) could be obtained. Moreover,
different stereoisomers could be obtained, depending on the
different chiral building blocks used as starting materials.
20
afforded the title compound (21 mg, 21%) as a colorless oil: [R]D
) +1.50 (c 1, CHCl3); 1H NMR (CDCl3) δ 1.22 (3H, d, J ) 5.95
Hz), 1.29-2.15 (18H, m), 3.63 (2H, t, J ) 6.33 Hz), 3.65-3.76
(1H, m), 4.07-4.19 (1H, m); MS (EI) m/z 136 (11), 121 (100), 98
(48), 83 (14), 77 (26), 55 (85). Anal. Calcd for C14H26O3: C, 69.38,
H, 10.81. Found: C, 69.57, H, 10.98.
Experimental Section
(R)-(tert-Butyldimethylsilanyloxy)non-1-en-4-ol (10). (-)-B-
Methoxydiisopinocamphenylborane (2.02 g, 6.4 mmol) was dis-
solved in anhydrous diethyl ether (6.4 mL) and cooled to -78 °C.
To the borinate was added dropwise 6.4 mL (6.4 mmol) of 1 M
allylmagnesium bromide in ethyl ether. The reaction mixture, after
being stirred for 15 min at -78 °C, was removed from the dry
ice-acetone bath and allowed to warm to 25 °C (∼1 h). The
formation of IpC2BCH2CHdCH2 was indicated by the precipitation
of the magnesium salts. The allylborane was cooled to -78 °C,
and 8 (1.48 g, 6.4 mmol) was added dropwise. The reaction mixture
was stirred for 1 h at -78 °C and then allowed to warm to 25 °C
(∼1 h). The mixture was treated with 3 M NaOH (4.7 mL) and 1.8
mL of 35% H2O2, and the contents were refluxed for 1 h. The
organic layer was separated, washed with water (4 mL) and brine
(4 mL), and dried over Na2SO4. Flash chromatography of the
residue using 95% hexane-5% ethyl acetate as eluent afforded the
(2′′R,5′′R,7′′R)-5,7-Dimethoxy-3-[5′-(2′′-methyl-1′′,6′′-dioxaspiro-
[4,5]dec-7′′-yl)pentylidene]isobenzofuran-1-one (15). To a solu-
tion of dimethyl phthalide-3-phosphonate 3 (51 mg, 0.17 mmol)
and 4 (48 mg, 0.2 mmol) in dry THF (2.5 mL) was added NaH
(10 mg of a 60% dispersion in mineral oil, 0.24 mmol), and the
mixture was stirred under nitrogen at room temperature for 24 h.
Water was added to react with the excess NaH and to dissolve
inorganic materials. The organic layer was separated and evaporated
in vacuo to give a residue which was taken up in CH2Cl2. The
resulting solution was washed with water, dried over Na2SO4, and
evaporated. Flash chromatography of the residue using 75%
hexane-25% ethyl acetate as eluent afforded the pure Z-isomer as
an oil (26 mg, 36%) and an E/Z mixture as an oil (18 mg, 26%):
1H NMR (CDCl3) (Z) δ 1.19 (3H, d, J ) 5.95 Hz), 1.15-1.90
(14H, m), 2.05-2.15 (2H, m), 2.37-2.46 (2H, m), 3.62-3.75 (1H,
m), 3.89 (3H, s), 3.92 (3H, s), 4.06-4.18 (1H, m), 5.53 (1H, t, J
) 7.82 Hz), 6.40 (1H, d, J ) 1.86 Hz), 6.59 (1H, d, J ) 1.86 Hz);
(E) δ 1.12-2.16 (19H, m), 2.45-2.55 (2H, m), 3.73-3.83 (1H,
m), 3.91 (3H, s), 3.96 (3H, s), 4.18-4.25 (1H, m), 5.78 (1H, t, J
) 8.19 Hz), 6.46 (1H, d, J ) 1.86 Hz), 6.79 (1H, d, J ) 1.86 Hz).
Anal. Calcd for C24H32O6: C, 69.21, H, 7.74. Found: C, 69.05, H,
7.56.
(+)-Spirolaxine 5-O-Methyl Ether (2). Compound 15 (7.5 mg,
0.018 mmol) dissolved in AcOH (1.2 mL) was hydrogenated at
room temperature with 10% Pd/C (13 mg) for 4 h to obtain, after
filtration and evaporation of the solvent, 7 mg of a crude.
Preparative HPLC of the residue afforded the title compound (45%)
as a yellow oil: 1H NMR (CDCl3) δ 0.75-2.19 (23H, m), 3.60-
3.72 (1H, m), 3.88 (3H, s), 3.94 (3H, s), 4.09-4.18 (1H, m), 5.29
(1H, dd, J ) 4.09, 7.44 Hz), 6.39 (1H, d, J ) 1.49 Hz), 6.40 (1H,
d, J ) 1.49 Hz). MS (EI) m/z 241 (18), 197 (12), 155 (25), 136
(41), 121 (100), 111 (48), 98 (100), 77 (67), 57 (66). HPLC
comparison: natural 2, column Chiral Daicel OB, eluent hexane-
i-PrOH (8:2) tR ) 13.36 min, flow rate 0.6 mL/min; synthetic 2,
column Chiral Daicel OB, tR ) 13.46 (50%), 14.83 (50%) min.
title compound (1.44 g, 82%) as a colorless oil: [R]20 ) +2.76
D
1
(c ) 1.12, Et2O); H NMR (CDCl3) δ 0.03 (6H, s), 0.88 (9H, s),
1.18-1.67 (8H, m), 2.39-2.02 (2H, m), 3.49-3.74 (3H, m), 5.12
(2H, d, J ) 12.65 Hz), 5.81 (1H, m). Anal. Calcd for C15H32O2Si:
C, 66.11, H, 11.84. Found: C, 66.26, H, 12.00.
(2′R,4′S,6′R,3′′R)-5-[4′-Chloro-6′-(3′′-hydroxybutyl)tetrahy-
dropyran-2′-yl]pentan-1-ol (12). To a stirred solution of TiCl4 (205
mg, 1.1 mmol) in dry CH2Cl2, which was cooled to -78 °C, was
added dropwise a solution of (R)-γ-valerolactol (100 mg, 0.98
mmol) in CH2Cl2 (1.8 mL). After 10 min, a solution of 10 (268
mg, 0.98 mmol) in CH2Cl2 (1.8 mL) was added. The mixture was
stirred at -78 °C for 4 h and at -20 °C for 1 h and then allowed
to warm to 0 °C. The reaction mixture was hydrolyzed with 6 mL
of saturated aqueous NH4Cl solution. The organic phase was
separated, washed with brine, and dried over Na2SO4. Evaporation
of the solvent in vacuo followed by flash chromatography of the
residue using 50% hexane-50% ethyl acetate as eluent afforded
the title compound (0.17 g, 63%) as a white solid: mp 63-64 °C;
[R]D20 ) -15 (c 1, CHCl3); 1H NMR (CDCl3) δ 1.17 (3H, d, J )
6.33 Hz), 1.20-1.86 (14H, m), 1.93-2.20 (2H, m), 3.20-3.38 (1H,
m), 3.63 (2H, t, J ) 6.33 Hz), 3.70-3.85 (1H, m), 3.89-4.06 (1H,
m); 13C NMR (150 MHz) (CDCl3) δ 23.4, 24.9, 25.5, 32.5, 32.6,
35.6, 35.9, 42.3, 42.6, 55.6, 62.4, 68.0, 76.7, 77.1; MS (EI) m/z
225 (40), 85 (100), 67 (30), 55 (55). Anal. Calcd for C14H27ClO3:
C, 60.31, H, 9.76. Found: C, 60.14, H, 9.87.
Acknowledgment. We are indebted to Sigma-Tau, Pomezia,
(2′R,6′R,3′′R)-5-[6′-(3′′-Hydroxybutyl)tetrahydropyran-2′-yl]-
pentan-1-ol (6). A solution of 12 (870 mg, 3.12 mmol) and NaBH4
(708 mg, 18.72 mmol) in dry DMSO (15 mL) was heated for 15 h
at 130 °C, then diluted with water (30 mL), and extracted with
diethyl ether (30 mL × 3). The organic phase was washed with
water, dried, and concentrated in vacuo to give the title compound
(728 mg, 96%) as a colorless oil: [R]D20 ) -1.4 (c 1, CHCl3); 1H
NMR (CDCl3) δ 1.16 (3H, d, J ) 6.33 Hz), 1.26-2.34 (18H, m),
3.25-3.37 (2H, m), 3.63 (2H, t, J ) 6.33 Hz), 3.70-3.85 (1H,
m); MS (EI) m/z 245 (M+, 100), 227 (35), 95 (35), 85 (80), 67
(50), 55 (95). Anal. Calcd for C14H28O3: C, 68.81, H, 11.55.
Found: C, 68.66, H, 11.34.
for financial support.
Supporting Information Available: Full details of the synthetic
procedures and characterization data for compounds 7, 8, 13, 14,
5, and 4, 1H NMR spectra of compounds 8, 12, and 15, diagnostic
region of the COESY and TROESY NMR spectra of compound
15, molecular model of compound 15, and CD spectra and 13C
NMR spectra of natural and synthetic 2. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO060839I
6280 J. Org. Chem., Vol. 71, No. 16, 2006